Altered developmental profile of the cortical head-direction signalin a rat model of Fragile X Syndrome

Abstract

Fragile X Syndrome (FXS) is a common inherited monogenic cause of autism spectrum disorder and intellectual disability (ASD/ID), but the neural mechanisms underlying its symptoms remain unclear. Here, we investigate the development of the head-direction (HD) system in a rat model of FXS (Fmr1-/y rats) and its role in spatial cognition. Using high-density silicon probes, we recorded neuronal activity in the postsubiculum (PoSub), a cortical hub of the HD system, during exploration and sleep in juvenile and adult Fmr1-/y and wild-type (WT) rats. Surprisingly, juvenile Fmr1-/y rats exhibited enhanced HD tuning characterized by sharper directional tuning curves and improved stability of the HD signal in relation to the external environment. This enhancement was intrinsic to the HD circuit and persisted across behavioral and sleep states. However, by adulthood, HD tuning in Fmr1-/y rats became unstable, with increased drift in the allocentric reference frame despite intact intrinsic HD dynamics. These findings reveal a transient enhancement of spatial coding in the HD system of juvenile Fmr1-/y rats, followed by a degradation in adulthood, mirroring the developmental regression often observed in autism. Overall, our work reveals network-level dysfunctions in FXS and their developmental trajectories.